Targeted overexpression of glutamate transporter-1 reduces seizures and attenuates pathological changes in a mouse model of epilepsy

Peterson, Allison R.; Garcia, Terese A.; Cullion, Kyle; Tiwari‐Woodruff, Seema K.; Pedapati, Ernest V.; Binder, Devin K.

doi:10.1016/j.nbd.2021.105443

Cited by 12 publications

(7 citation statements)

References 53 publications

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“…In previous works, upregulation of GLT1 expression decreased the glutamate concentration in the synaptic cleft and had a neuroprotective effect [18,26]. It was also beneficial in epilepsy, stroke, hypoxia, and neurodegeneration, pointing to the potential role of GLT1 as a pharmacological target for treating these disorders [5,9,11]. CTX treatment also reduced behavioral impairment in multiple diseases.…”

Section: Discussionmentioning

confidence: 85%

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Ceftriaxone Treatment Weakens Long-Term Synaptic Potentiation in the Hippocampus of Young Rats

Postnikova

Malkin

Захарова

et al. 2021

IJMS

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Disrupted glutamate clearance in the synaptic cleft leads to synaptic dysfunction and neurological diseases. Decreased glutamate removal from the synaptic cleft is known to cause excitotoxicity. Data on the physiological effects of increased glutamate clearance are contradictory. This study investigated the consequences of ceftriaxone (CTX), an enhancer of glutamate transporter 1 expression, treatment on long-term synaptic potentiation (LTP) in the hippocampus of young rats. In this study, 5-day administration of CTX (200 mg/kg) significantly weakened LTP in CA3-CA1 synapses. As shown by electrophysiological recordings, LTP attenuation was associated with weakening of N-Methyl-D-aspartate receptor (NMDAR)-dependent signaling in synapses. However, PCR analysis did not show downregulation of NMDAR subunits or changes in the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits. We assume that extracellular burst stimulation activates fewer synapses in CTX-treated animals because increased glutamate reuptake results in reduced spillover, and neighboring synapses do not participate in neurotransmission. Attenuation of LTP was not accompanied by noticeable behavioral changes in the CTX group, with no behavioral abnormalities observed in the open field test or Morris water maze test. Thus, our experiments show that increased glutamate clearance can impair long-term synaptic plasticity and that this phenomenon can be considered a potential side effect of CTX treatment.

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Section: Discussionmentioning

confidence: 85%

“…GLT1 transports more than 90% of synaptic glutamate in the hippocampus, and GLT1 accounts for 80% of EAAT molecules [9,10]. Therefore, enhancing GLT1 expression with pharmacological and genetic methods is considered a promising therapeutic option for diseases associated with impaired glutamate transport [5,10,11].…”

Section: Introductionmentioning

confidence: 99%

Ceftriaxone Treatment Weakens Long-Term Synaptic Potentiation in the Hippocampus of Young Rats

Postnikova

Malkin

Захарова

et al. 2021

IJMS

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“… 67 Upregulation of glutamate transporter in astrocyte has been shown to reduce seizure frequency in a mouse model of temporal lobe epilepsy induced by intrahippocampal kainic acid. 68 This is interesting and could be examined in future studies. Another limitation of the present study is that the mechanism of FMT in reducing spasms remains unclear.…”

Section: Discussionmentioning

confidence: 91%

Seizure modulation by the gut microbiota and tryptophan-kynurenine metabolism in an animal model of infantile spasms

Choudhary

Mayengbam

et al. 2022

eBioMedicine

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Background The infantile spasms syndrome is an early-onset epileptic encephalopathy presenting in the first 2 years of life, often with severe developmental consequences. The role of the gut microbiota and metabolism in infantile spasms remains unexplored.Methods Employing a brain injury neonatal rat model of infantile spasms intractable to anticonvulsant medication treatments, we determined how the ketogenic diet and antibiotics affected specific microbial communities and the resultant circulating factors that confer spasms protection in the infantile spasms model. To confirm a role of kynurenine metabolism pathway in spasms protection, indoleamine 2,3-dioxygenase 1 was pharmacologically inhibited and comprehensive metabolomics was applied.Findings We show that antibiotics reduced spasms and improved the effectiveness of the ketogenic diet when given in combination. Examination of the gut microbiota and metabolomics showed the downregulation of indoleamine 2,3-dioxygenase 1 and upregulation of hippocampal kynurenic acid, a metabolite with antiepileptic effects. To further test the involvement of indoleamine 2,3-dioxygenase 1, a specific antagonist 1-methyltryptophan and minocycline, an antibiotic and inhibitor of kynurenine formation from tryptophan, were administered, respectively. Both treatments were effective in reducing spasms and elevating hippocampal kynurenic acid. A fecal microbiota transplant experiment was then performed to examine the contribution of the gut microbiota on spasm mitigation. Transplant of feces of ketogenic diet animals into normal diet animals was effective in reducing spasms.Interpretation These results highlight the importance of tryptophan-kynurenine metabolism in infantile spasms and provide evidence for new-targeted therapies such as indoleamine 2,3-dioxygenase 1 inhibition or microbiota manipulation to promote kynurenic acid production as a strategy to reduce spasms in infantile spasms.

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“…Targeting glutamate uptake has emerged as a promising strategy for the treatment of epilepsy. Targeted overexpression of glutamate transporter‐1 reduces seizures and attenuates pathological changes in a mouse model of epilepsy [41]. When extracellular glutamate concentrations rise to abnormal levels, glutamate receptor over‐activation and subsequent calcium influx into postsynaptic neurons trigger the cell death pathway.…”

Section: Discussionmentioning

confidence: 99%

Construction and analysis of a competing endogenous RNA network associated with circRNAs dysregulated in medial temporal lobe epilepsy

Zhu

et al. 2022

Epileptic Disorders

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Objective. The aetiology and pathogenesis of medial temporal lobe epilepsy (MTLE) remain unclear, and effective treatments are lacking. The involvement of a dysregulated competing endogenous RNA (ceRNA) network in MTLE is only partially understood. The purpose of this study was to investigate MTLE regulatory networks composed of messenger RNAs (mRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) through a ceRNA network map. Methods. RNA sequencing (RNA-seq) and small RNA-seq were used to detect mRNAs, circRNAs, miRNAs, and lncRNAs differentially expressed between postoperation hippocampal tissues of MTLE patients (n = 3) and paracancer tissues (n = 3). We performed bioinformatics analysis to identify differentially expressed RNAs and construct the corresponding ceRNA network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of differentially expressed RNAs were conducted to explore the biological processes and pathways involved in MTLE. Results. We identified 352 differentially expressed mRNAs, 179 circRNAs, and 42 miRNAs in MTLE. A ceRNA network composed of mRNAs, circRNAs, and miRNAs was constructed. GO and KEGG analysis of the network suggested a key role of synapses and mTOR, cAMP, ErbB, FoxO, and HIF-1 signalling pathways in MTLE. Significance. We identify a new circRNA-miRNA-mRNA ceRNA network in MTLE. These results can help clarify the aetiology of MTLE and identify targeted molecular therapies.

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Targeted overexpression of glutamate transporter-1 reduces seizures and attenuates pathological changes in a mouse model of epilepsy

Cited by 12 publications

References 53 publications

Ceftriaxone Treatment Weakens Long-Term Synaptic Potentiation in the Hippocampus of Young Rats

Ceftriaxone Treatment Weakens Long-Term Synaptic Potentiation in the Hippocampus of Young Rats

Seizure modulation by the gut microbiota and tryptophan-kynurenine metabolism in an animal model of infantile spasms

Construction and analysis of a competing endogenous RNA network associated with circRNAs dysregulated in medial temporal lobe epilepsy

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